Ultrafiltration (UF) and microfiltration (MF) membranes have become essential to the separation and purification of macromolecules including the manufacture of biomolecules. Biomolecular manufacturing, regardless of its scale, generally employs one or more steps using filtration.
In one class of membrane separations, the species of interest is that which is retained by the membrane, in which case the objective of the separation is typically to remove smaller contaminants, to concentrate the solution, or to affect a buffer exchange using diafiltration. In another class of membrane separations, the species of interest is that which permeates through the filter, and the objective is typically to retain or remove larger contaminants. In MF, the retained species are generally particulates, organelles, bacteria or other microorganisms, while those that permeate are proteins, colloids, peptides, small molecules and ions. In UF the retained species are typically proteins and, in general, macromolecules, while those that permeate are peptides, ions and, in general, small molecules.
Permeation flux, also referred to as flux, is the flow rate of a solution through a filter per unit of membrane area. The ability to maintain a reasonably high flux is essential in the membrane separation filtration process. Low flux can result in long filtration times or require large filter assemblies, resulting in increased cost and large hold-up volumes retained in the modules and associated filter system equipment. The filtration process itself induces the creation of a highly concentrated layer of the retained species on the surface of the membrane, a phenomenon referred to as “concentration polarization,” which reduces the flux from initial membrane conditions. In the absence of counter measures, the accumulation of retained particles or solutes on the surface of the membrane results in decreased flux and if not corrected the filtering process ceases to function efficiently. One conventional approach to overcoming the effects of concentration polarization in the practice of microfiltration and ultrafiltration is to operate the separation process in tangential flow filtration (TFF) mode.
TFF filters, modules and systems include devices having flow channels formed by membranes through which the feed stream flows tangentially to the surface of the membrane. The tangential flow induces a sweeping action that removes the retained species and mitigates accumulation, thereby maintaining a high and stable flux. Because higher tangential velocities produce higher fluxes, the conventional practice of TFF requires the use of high velocities in the flow channels, which in turn result in very high feed rates. In conventional systems short channels are also required to maintain reasonable feed pressures. These high feed rates in combination with relatively short channels result in only a small fraction of the feed being permeated, typically less than 10% and often less than 5%. The fraction of feed permeated in passing through a module is also referred to as conversion and the resulting increase in the concentration of compounds that do not permeate is known as the concentration factor or concentration. Low conversion means that the bulk of the feed stream exits the module as retentate concentrated in the retained solutes by only a few percent. Since many UF separations require high overall process conversions, as high as 99%, the retentate is typically recirculated back to the feed tank or directly to the inlet of that module for further permeation and concentration. In addition to the large pumps, pipes and flow components required in conventional TFF, systems with these recirculation loops are complicated by the requirement of additional piping, storage, heat exchangers, valves, sensors and control instrumentation.
In the pharmaceutical, vaccine production, and biotechnology industries, system or components used in manufacturing processes that are disposed of after a single use are known as “single use” or “disposable” products. These types of products are increasingly popular for a number of reasons, including the elimination of the need to clean the systems prior to the next use, the elimination of possible cross-contamination between successive batches, the elimination of the need to validate the performance of the product after reuse and reduction in the capital cost of the equipment. The principal drawback to the use of these products is the cost incurred in their purchase and disposal after a single use.
Ultrafiltration and microfiltration processes in the pharmaceutical and biotechnology industries are generally carried out in a tangential flow mode using batch systems. The fluid is pumped from a feed vessel through a suitable membrane module and back to the same vessel in order to achieve the necessary conversion or concentration. In some processes a new solvent, called the diafiltrate, is added to this vessel to compensate completely or partially for the fluid that permeates from the module, thereby replacing the original solvent with the new one being added. These tangential flow systems and processes are difficult to design for single use because the high volumetric flow rates through the module require large circulation pumps, large pipes and large ancillary hydraulic components such as valves, heat exchangers, etc. In reuse systems, these components are typically made of stainless steel and their disposal after a single use is typically economically prohibitive. Plastic components used in conventional single-use systems limit the combination of high pressure and large size. Batch filtration systems can be driven by peristaltic pumps, which provide a disposable fluid path and do not require the cleaning of the pumps or their disposal, but do require the use of large pumps and large diameter tubing. The complexity of the pumping systems also increases costs.
In the batch tangential flow operating mode, there are a number of approaches to controlling the concentration process. Since there are three fluids associated with the operation of tangential flow modules in a concentration mode—feed, retentate and permeate—it is only possible to control two associated parameters (i.e., there are only two degrees of freedom in the operation of such a module). Common pairs of parameters that are set or controlled are: feed flow rate and retentate pressure of module; feed flow rate and average trans-membrane pressure; or feed flow rate and permeation rate. The feed rate is generally controlled by means of the speed of the feed pump or a throttling valve between the pump outlet and the inlet of the module. The retentate pressure is controlled by means of a throttling valve on the module outlet. Trans-membrane pressure can be controlled by use of a throttling valve on the permeate outlet in combination with the inlet and outlet pressures of the module. There are other ways of implementing concentration control, some of which are described in U.S. Pat. Nos. 6,607,669 and 6,350,382. These patents teach weighing the feed in order to monitor a batch/recirculation process controlled by valves and pumps. These systems are generally not designed for single use because of the expensive valves and large circulation pumps, and the complexity resulting from the existence of a recirculation loop.
In batch tangential flow ultrafiltration or microfiltration diafiltrate is generally added to the feed tank in proportion to the rate of permeation. Most commonly the rate of diafiltrate addition is set equal to the rate of permeation. This is accomplished by pumping diafiltrate to the feed tank so as to keep the fluid level fixed. This is referred to as “constant volume diafiltration.”
In single pass tangential flow processes operated at a high concentration factor a number of modules are connected in series forming a filtration train comprising multiple stages. A detailed description of the structure and operation of a single pass filtration (SPF) module is discussed in “Method And Apparatus For The Filtration Of Biological Solutions,” U.S. Pat. No. 7,384,549, and “Method And Apparatus For The Filtration Of Biological Samples,” U.S. Pat. No. 7,510,654, which are herein fully incorporated by reference. Control of the overall concentration factor is most commonly affected by using a feed pump and a retentate pump, operated at a fixed ratio of their flow rates, and referred to as feed-to-retentate flow-ratio-control (“FRC”). FRC represents a first control parameter. A second control parameter in such a system is typically the feed rate (alternatively the retentate rate can be controlled). It is, of course, also possible to control the average trans-membrane pressure of the entire system. In this case it is possible to use a control system based on controlling the feed rate in combination with control of the retentate pressure. Alternatively, the pressure on the combined permeate stream (i.e., the combined stream of all of the modules) can be throttled by means of a valve or by means of a pump on the combined permeate stream. It is also possible to control the individual permeation rate of any one or all of the stages of a staged system as long as the number of control parameters is not greater than the degrees of freedom in the staged single-pass system, which is equal to the number of stages plus one.
In diafiltration processes utilizing single pass systems, diafiltrate is added to some of the stages. The rate of diafiltrate addition to each stage can be controlled by controlling the total rate of diafiltrate addition, by any suitable means, in combination with the use of a diafiltrate distributor, an array of hydraulic restrictors, effectively distributing the diafiltrate among the stages accepting diafiltration. Generally it is desirable to operate such a single-pass diafiltration process in “constant volume” mode in each stage, whereby the rate of diafiltrate addition to each stage is made approximately equal to the rate of permeation from that stage.
The most common diafiltration flow configuration in single pass TFF processes is the “cross-current” configuration, according to which fresh diafiltrate is added to each stage. A “counter-current” configuration is sometimes used to reduce diafiltrate requirements. In counter current diafiltration fresh diafiltrate is added to one or more of the stages proximal to the retentate outlet and permeate from one or more of these stages serves as diafiltrate to one or more of the preceding stages. In both these forms of single-pass staged diafiltration process the total amount of diafiltrate required to achieve a given degree of removal of the permeating impurity decreases as the total membrane area is subdivided into a larger number of stages. The practical limit on the number of stages used is given by the increased cost as the total membrane area is divided into smaller stages.
TFF systems operated as batch systems require the use of large circulation pumps and associated piping. This results in large hold-up volumes and the additional complexity of tanks, valves, and instrumentation required to effectively operate a process with a recirculation stream. Because of the large size of the pumps and the additional complexity, such single-use systems (i.e., based on conventional TFF processes) are generally economically prohibitive.